Transmembrane 4 L6 family member 5 (TM4SF5 or L6H) is a protein that is homologous to a tumor-associated antigen L6 (TM4SF1), which is a member of the transmembrane 4 L6 superfamily. The transmembrane 4 L6 superfamily further includes IL-TMP and L6D. The L6 antigen (TM4SF1) is highly expressed on colon, lung, breast, and ovarian carcinomas. The TM4SF5 protein (L6H), homologous to the L6 antigen (TM4SF1), is also highly expressed in several types of cancer including pancreatic, gastric, colon and liver carcinomas (Muller-Pillasch, F. et al., Gene, 208:25, 1998; Pascual-Le Tallec, L. et al., J. Clin. Endocrinol. Metab., 87:501, 2002). TM4SF5 mRNA is expressed at lower levels in gastric cancer tissues compared to the L6 antigen (TM4SF1), but is overexpressed in liver and gastric carcinoma cell lines (Kaneko, R. et al., Am. J. Gastroenterol., 96(12):3457, 2001).
Based on the research results, TM4SF5 has been recently registered as a novel oncogene, as disclosed in U.S. Pat. No. 6,350,581 B1, in which TM4SF5 is named a human tumor-associated antigen (TUAN). The present inventors recently found, through the expression of TM4SF5 in COST cells, that TM4SF5-mediated actin reorganization, focal adhesion formation and focal adhesion kinase (FAK) phosphorylation at Tyr925 are induced via integrin α2 subunit, and are regulated (inhibited) by treatment with serum containing cell growth factors (Lee, S. Y. et al., Exp. Cell Res., 312:2983, 2006).
However, the molecular mechanism of TM4SF5-mediated tumorigenesis is poorly understood. The functions of TM4SF5 at the molecular level are unknown, and the evidence for the carcinogenic role of TM4SF5 has not been presented at the biochemical and cell biological levels.
On the other hand, chalcones are widely distributed in edible plants and are known as precursors of flavonoids or isoflavonoids. Derivatives of such chalcones are constituents of yellow pigments of plants, which affect plant color and protect plants from harmful ultraviolet rays (Methodology of Natural Product Chemistry, W. S. Woo, Seoul National University Press). Chalcone derivatives are abundant in Coreopsis plants, which is the genus of the family Asteraceae. Representative chalcones include 2′,6′-dihydroxy-4′-methoxychalcone and carthamine, and are contained in plants including cinnamon, safflower and pepper. Dihydrochalcone is contained mainly in certain plant species of the families Rosaceae and Ericaceae. Phloridzin is a dihydrochalcone that is found primarily in apple peels, and is responsible for the resistance of apple trees to diseases.
Such chalcone derivatives have been known to have various pharmaceutical activities, such as antiprotozoal activity (Liu, M. et al., J. Med. Chem., 44:4443, 2001), anti-inflammatory activity (Babu, M. A. et al., Bioorg. Med. Chem., 10:4035, 2003), immunomodulation (Barfod, L. et al., Int. Immunopharmacol., 2:545, 2002), inhibition of nitric oxide production (Rojas, J. et al., Bioorg. Med. Chem. Lett., 12:1951, 2002), anticancer activity (Kumar, S. K. et al., J. Med. Chem., 46:2813, 2003), and anti-HIV activity (Artico, M. et al., J. Med. Chem., 41:3984, 1998).
In addition, Korean Patent Publication 10-2003-0036993 discloses that chalcone compounds have inhibitory activity against matrix metalloproteinase (MMP), which degrades components of basement membrane (Park, K. H. et al., Bioorg. Med. Chem. Lett., 15:5514, 2004).
Among chalcone compounds, sulfonamide- or sulfonate-substituted chalcone derivatives have been reported to have specific biological properties, not shown in naturally occurring chalcones. In particular, the present inventors found that sulfonamide chalcone derivatives have strong inhibitory activity against α-glucosidase (Park, K. H. et al., Bioorg. Med. Chem. Lett., 15:5514, 2004; Korean Patent Publication 10-0751899). The present inventors also recently reported sulfonate chalcone derivatives as selective K(+) channel blockers (Park, K. H. et al., Bioorg. Med. Chem. Lett., 2007).
However, there is no report stating that sulfonamide or sulfonate chalcone derivatives have anticancer activity through a mechanism of inhibiting the oncogenic TM4SF5 protein.
In this regard, the present inventors have conducted intensive and thorough research, thus resulting in the finding that the oncogenic potential of TM4SF5, shown in human carcinoma cells, is due to its ability to promote epithelial-mesenchymal transition (EMT), leading to the loss of contact inhibition. Also, the present inventors found that the oncogenic function of TM4SF5 is mediated via a new pathway, which is composed of a series of steps that include focal adhesion kinase (FAK) phosphorylation and cytosolic p27kip1 accumulation, leading to inhibition of RhoA activity and changes in cell morphology. Based on this finding, the present inventors have made many efforts to screen anticancer substances inhibiting TM4SF5-mediated tumor formation, development and metastasis, thereby leading to the present invention.